WO2008096145A1 - Procédé de fabrication du chlorhydrate d'éthyl-n-(2, 3-dichloro-6-nitrobenzyl) glycine - Google Patents

Procédé de fabrication du chlorhydrate d'éthyl-n-(2, 3-dichloro-6-nitrobenzyl) glycine Download PDF

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Publication number
WO2008096145A1
WO2008096145A1 PCT/GB2008/000430 GB2008000430W WO2008096145A1 WO 2008096145 A1 WO2008096145 A1 WO 2008096145A1 GB 2008000430 W GB2008000430 W GB 2008000430W WO 2008096145 A1 WO2008096145 A1 WO 2008096145A1
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Prior art keywords
compound
formula
group
process according
alkyl
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Application number
PCT/GB2008/000430
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English (en)
Inventor
Srinivas Laxminarayan Pathi
Rajendra Narayanrao Kankan
Dharmaraj Ramachandra Rao
Original Assignee
Cipla Limited
Curtis, Philip, Anthony
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cipla Limited, Curtis, Philip, Anthony filed Critical Cipla Limited
Priority to US12/525,760 priority Critical patent/US8133996B2/en
Priority to JP2009548737A priority patent/JP2010518060A/ja
Priority to CA002675265A priority patent/CA2675265A1/fr
Priority to AU2008212668A priority patent/AU2008212668B2/en
Priority to NZ578561A priority patent/NZ578561A/en
Priority to EP08702079A priority patent/EP2114856A1/fr
Publication of WO2008096145A1 publication Critical patent/WO2008096145A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/07—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/18—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/18—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C07C309/66—Methanesulfonates

Definitions

  • the present invention relates to an improved process for the preparation of ethyl-N-(2, 3- dichloro-6-nitrobenzyl)glycine hydrochloride which is a key intermediate used in the preparation of anagrelide, (6,7-dichloro-l,5-dihydroimidazo[2,l-b]qumazolin-2(3H)-one.
  • Anagrelide is a potent reducer of platelet count induced by a variety of aggregating agents and has the following structure
  • US 5801245 discloses process for the preparation of ethyl-N-(2,3-dichloro-6- nitrobenzyl)glycine hydrochloride from 2,3-dichloro toluene as depicted in Scheme II.
  • the reaction involves a radical halogenation of the toluene group.
  • the material is purified by column chromatography at each stage which makes the process more tedious and it is not viable industrially.
  • a chromatographic solvent such as chloroform (which is a known carcinogen)
  • chloroform which is a known carcinogen
  • US 2003/0060630 discloses a method for making ethyl-N-(2, 3-dichloro-6-nitro benzyl)glycine hydrochloride form 2,3-dichloro benzaldehyde as depicted in Scheme III.
  • step (b) the reduction reaction is earned out in high boiling solvents like toluene.
  • the reduction in step (b) and the chlorination in step (c) are sluggish.
  • the chlorination reaction is exothermic and uncontrollable, which leads to formation of more impurities and thereby resulting in low yield (page 4, column 2, and page 5, column 1 : 65 %) .
  • this prior art process is not viable for industrial scale up.
  • the present invention relates to a new process for the synthesis of Ethyl-N-(2, 3-dichloro-6- nitrobenzyl)glycine hydrochloride.
  • It is an object of the present invention is to provide a novel process for the synthesis of the intermediate ethyl N-(2, 3-dichloro-6-nitrobenzyl)glycine hydrochloride.
  • Another object of the present invention is to provide novel process for synthesis of anagrelide.
  • Another object of the present invention is to provide a simple novel process which is useful for application on an industrial scale.
  • the present invention provides a new process for the synthesis of ethyl N-(2,3-dichloro-6- nitrobenzyl)glycine hydrochloride, a compound of Formula (I)
  • R constitutes a suitable leaving group, which may not be hydrogen.
  • the group R is selected from:
  • R 1 is a substituted or unsubstituted alkyl.
  • R 1 is preferably Ci to C 6 , more preferably Ci to C 4 straight or branched chain alkyl group. Most preferably R 1 is methyl.
  • ii) -CH 2 Ar where Ar stands for aryl, preferably a substituted or unsubstituted phenyl group.
  • iii) -COOR 2 where R 2 is alkyl or aryl.
  • R 2 is alkyl it is preferably Ci to C 6 , more preferably Ci to C 4 straight or branched chain alkyl.
  • R 2 is alkyl, it is most preferably roefh) 1 .
  • the aryl group is prefe-rr.h'y a substituted or ⁇ nsubs?it" + ⁇ d phenyl group. iv) sulfonates such as -SO 2 R 3 , where R 3 is alkyl or aryl.
  • R 3 is alkyl it is preferably Ci to C 6 , more preferably Ci to C 4 straight or branched chain alkyl.
  • R 3 is alkyl, it is most preferably methyl.
  • the aryl group is preferably a substituted or unsubstituted phenyl group.
  • the most preferred -O-R groups in formula (V) are mesylate, besylate and tosylate.
  • step (iii) Alkylating the compound of Formula (V) with glycine ethyl ester in a suitable solvent, using a base, and then converting to a salt, preferably the hydrochoride salt, in a suitable solvent, to obtain compound of Formula I.
  • step (i) is optional, in that the compound of formula (IV) may be provided by any suitable means.
  • R is a suitable leaving group, which may not be hydrogen, said process comprising reacting a compound of formula (IV)
  • the .taction is carried o ⁇ in tlu presence of an all' ⁇ 1 oi ⁇ .; l sulphonyl halide, especially a methyl sulphonyl halide, such as methyl sulphonyl chloride.
  • the reaction is carried out in the presence of a base, such as triethylamine.
  • the reaction is earned out at a temperature of 35°C, or less.
  • processing comprising alkylating a compound of Formula (V) where R constitutes a suitable leaving group, which may not be hydrogen (preferably as described above) with glycine ethyl ester in a suitable solvent, using a base.
  • the compound of formula (I 1 ) may be converted to a salt in the presence of a suitable solvent. Most preferably, the compound of formula (I 1 ) is converted to the hydrochloride salt in a suitable solvent, to obtain compound of Formula (I).
  • the reaction temperature of the alkylation step is preferably 60°C, or lower, more preferably 4O 0 C, or lower.
  • R is a suitable leaving group, which may not be hydrogen, and is preferably as described above.
  • the present invention provides a process to prepare anagrelide of Formula (II) which comprises the following steps. (i) Forming a salt of the compound of formula I' (the hydrochloride salt is preferred, formula I) using the process described above;
  • halide is chloro, bromo or iodo
  • the anagrelide formed by the processes desc ⁇ oed above may be combined with a suitable carrier to make a pharmaceutical composition.
  • Such compositions may be used to reduce platelet count induced by a variety of aggregating agents.
  • R represents a suitable leaving group, wherein R is not hydrogen and preferably has the meaning described above in relation f o fornr.'.ir. (V)
  • the reducing agent is preferably selected from sodium borohydride, potassium borohydride, sodium cyanoborohydride and tetramethyl ammonium borohydride.
  • the reaction is preferably carried out in a solvent, which is preferably a Ci to C 6 straight chain or branched chain alcohol, especially methanol, ethanol, isopropanol or n-butanol; or a chlorinated solvent such as chloroform, methylene chloride, carbon tetrachloride, ethylene chloride, with methylene chloride being preferred.
  • the reaction is preferably carried out at a temperature ranging from O 0 C to the reflux temperature of the solvent., and the reaction time may vary from 1 to 3 hrs.
  • suitable protecting group R as discussed above in relation to formula (IV) using variety of methods.
  • organic or inorganic bases may be employed, such as triethylamine, pyridine or potassium carbonate, with triethylamine being preferred.
  • one method includes reacting 2,3-dichloro-6-nitro benzyl alcohol - Formula (IV) - with alkyl or aryl sulphonyl halide in the presence of a base, such as triethylamine or the like, preferably at a temperature of 35 0 C, or less, for a time preferably less than 8 hours.
  • a base such as triethylamine or the like
  • the sulfonyl halide is preferably added to the compound of Formula (IV) over an extended period of time at a temperature of 30°C, or less, with stirring.
  • the reaction is not exothermic, which avoids impurity formation.
  • the organic layer may then be separated, washed with an acid and neutralized with a base, then concentrated to obtain the compound of Formula (V).
  • the alkyl sulphonyl halide is preferably Ci to C 6 , more preferably Ci to C 4 straight or branched chain alkyl.
  • the alkyl sulphonyl halide is most preferably methyl suphonyl halide.
  • the preferred aryl groups are phenyl and p-toluyl.
  • Steps (i) and ( ii ) are preferably carried out without isolating the alcohol of Formula (IV).
  • the compound of Formula (V) is alkylated with glycineethylester in an organic solvent, such as acetonitrile, using base and a catalyst preferably, dimethyl amino pyridine.
  • Suitable bases for this reaction are carbonates or alkali metal hydroxides, preferably anhydrous potassium carbonate.
  • the reaction is carried out at a temperature less than or equal to 60 0 C, more preferably less than or equal to 4O 0 C.
  • reaction mass is filtered, and concentrated under vacuum to obtain ethyl-N-(2,3-dichloro-6-nitrobenzyl) glycine, which is further converted to hydrochloride salt in suitable organic solvent such as ethyl acetate to obtain ethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride, a compound of Formula (I)
  • the reaction can be carried out at low temperature of 37-40°C in acetonitrile as solvent , potassium carbonate as base and 0.2% w/w dimethyl amino pyridine as catalyst . Due to the low reaction temperature, a relatively small level of impurities are formed giving high yield and purity - Efficiency 75.52%.
  • intermediate ethyl-N-(2,3-dichloro-6-nitrobenzyl) glycine hydrochloride of Formula (I), prepared by using process of the present invention, is converted to anagrelide by
  • the preferred reduction is metal reduction using stannous chloride and a preferred acid is hydrochloric acid.
  • the reaction is preferably carried out at a temperature of 50°C, or less. After completion of the reaction,the reaction mass is filtered, suspended in water and basif ⁇ ed to obtain an amine of Formula (VI).
  • the compound, ethyl-N-(5, 6-dichloro-3,4-dihydro-2(lH) iminoquinazoline-3- acetate hydrobromide of Formula (VII) is readily converted to anagrelide of Formula (II) with an organic base, such as triethylamine or dimethylaniline.
  • the reaction may be carried out in an inert solvent.
  • the intermediate compound of Formula (V) represents a novel compound, per se, and this novel intermediate forms further aspects of the present invention.
  • the reaction is carried out by protecting the hydroxymethyl functionality of compound of formula (IV).
  • methane sulphonyl chloride in methylene chloride, the reaction was less exothermic than in the prior art, and was more controllable with less impurity formation.
  • Overall yield - 76% ( From compound III to compound I) with HPLC purity of 98.5%
  • the solids thus obtained were suspended in water (2.9 liters), adjusted the pH of the reaction mass to 8.0-9.0 using potassium carbonate solution (prepared by dissolving 376 gms of potassium carbonate in 4.25 liters of water) at 0-5 0 C, extracted into toluene (3.0 liters> ⁇ 3), dried over sodium sulphate and clarified.
  • potassium carbonate solution prepared by dissolving 376 gms of potassium carbonate in 4.25 liters of water

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention porte sur un procédé de préparation d'anagrélide et de préparation d'intermédiaires pour utilisation dans la préparation de l'anagrélide. L'invention porte également sur les intermédiaires en tant que tels, en particulier sur des composés de formule (V) où R constitue un groupe partant approprié qui peut ne pas être l'hydrogène. Le groupe R peut être choisi parmi (i) -SiR13, (ii) -CH2Ar, (iii) -COOR2, et (iv) des sulfonates tels que -SO2R3.
PCT/GB2008/000430 2007-02-06 2008-02-06 Procédé de fabrication du chlorhydrate d'éthyl-n-(2, 3-dichloro-6-nitrobenzyl) glycine WO2008096145A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US12/525,760 US8133996B2 (en) 2007-02-06 2008-02-06 Process for the preparation of ethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride
JP2009548737A JP2010518060A (ja) 2007-02-06 2008-02-06 エチル−ｎ−（２，３−ジクロロ−６−ニトロベンジル）グリシン塩酸塩の製造方法
CA002675265A CA2675265A1 (fr) 2007-02-06 2008-02-06 Procede de fabrication du chlorhydrate d'ethyl-n-(2, 3-dichloro-6-nitrobenzyl) glycine
AU2008212668A AU2008212668B2 (en) 2007-02-06 2008-02-06 Process for the preparation of ethyl-N-(2, 3-dichloro-6-nitrobenzyl) glycine hydrochloride
NZ578561A NZ578561A (en) 2007-02-06 2008-02-06 Process for the preparation of ethyl-n-(2,3-dichloro-6-nitrobenzyl) glycine hydrochloride
EP08702079A EP2114856A1 (fr) 2007-02-06 2008-02-06 Procede de fabrication du chlorhydrate d'ethyl-n-(2, 3-dichloro-6-nitrobenzyl) glycine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN215/MUM/2007 2007-02-06
IN215MU2007 2007-02-06

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PCT/GB2008/000430 WO2008096145A1 (fr) 2007-02-06 2008-02-06 Procédé de fabrication du chlorhydrate d'éthyl-n-(2, 3-dichloro-6-nitrobenzyl) glycine

Country Status (9)

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US (1) US8133996B2 (fr)
EP (1) EP2114856A1 (fr)
JP (1) JP2010518060A (fr)
KR (1) KR20090115151A (fr)
AU (1) AU2008212668B2 (fr)
CA (1) CA2675265A1 (fr)
NZ (1) NZ578561A (fr)
WO (1) WO2008096145A1 (fr)
ZA (1) ZA200904906B (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010070318A1 (fr) * 2008-12-17 2010-06-24 Shire Llc Procédé de préparation d'anagrélide et de ses analogues
US8133996B2 (en) 2007-02-06 2012-03-13 Cipla Limited Process for the preparation of ethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride
CN107108464A (zh) * 2015-01-13 2017-08-29 日产化学工业株式会社 芳香族胺化合物的制造方法
CN107108463A (zh) * 2015-01-13 2017-08-29 日产化学工业株式会社 反应混合物中的锡化合物的处理方法
WO2024180371A1 (fr) * 2023-03-02 2024-09-06 Mohammadi Ali Synthèse et purification du principe pharmaceutique actif de chlorhydrate d'anagrélide et de tous ses intermédiaires

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2044720B1 (fr) 2006-07-25 2015-10-21 Electronics and Telecommunications Research Institute Procédé de recherche de cellule, procédé d'émission de trame à liaison aval, appareil associé et structure de trame à liaison aval
US11009339B2 (en) 2018-08-23 2021-05-18 Applied Materials, Inc. Measurement of thickness of thermal barrier coatings using 3D imaging and surface subtraction methods for objects with complex geometries

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US4208521A (en) * 1978-07-31 1980-06-17 Bristol-Myers Company Process for the preparation of imidazo[2,1-b]quinazolinones
EP0514917A1 (fr) * 1991-05-22 1992-11-25 Egis Gyogyszergyar Procédé et intermediaires de 2-(cyanoimino)-quinazoline pour la préparation de 6,7-di-(chloro)-1,5-di(hydro)-imidazo-[2,1-b]quin-azolin-2[3]-one aissi que procédé de préparation de 2-(cyanoimino)-quinazoline
US20030060630A1 (en) * 2000-07-26 2003-03-27 Shire Us Inc. Method for the manufacture of Anagrelide

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US4146718A (en) 1978-04-10 1979-03-27 Bristol-Myers Company Alkyl 5,6-dichloro-3,4-dihydro-2(1h)-iminoquinazoline-3-acetate hydrohalides
JPS60248648A (ja) * 1984-05-23 1985-12-09 Sumitomo Chem Co Ltd シクロヘプテニルアミン系化合物およびその塩、およびそれらを有効成分とする土壌病害防除剤
CA2171073A1 (fr) 1995-12-04 1997-06-05 Philip C. Lang Methode de preparation d'ethyl-n-(2,3-dichloro-6-nitrobenzyl)glycine
AU769890B2 (en) * 1998-12-04 2004-02-05 Fujisawa Pharmaceutical Co., Ltd. Sulfonamide compounds and uses thereof as medicines
WO2008096145A1 (fr) 2007-02-06 2008-08-14 Cipla Limited Procédé de fabrication du chlorhydrate d'éthyl-n-(2, 3-dichloro-6-nitrobenzyl) glycine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4208521A (en) * 1978-07-31 1980-06-17 Bristol-Myers Company Process for the preparation of imidazo[2,1-b]quinazolinones
EP0514917A1 (fr) * 1991-05-22 1992-11-25 Egis Gyogyszergyar Procédé et intermediaires de 2-(cyanoimino)-quinazoline pour la préparation de 6,7-di-(chloro)-1,5-di(hydro)-imidazo-[2,1-b]quin-azolin-2[3]-one aissi que procédé de préparation de 2-(cyanoimino)-quinazoline
US20030060630A1 (en) * 2000-07-26 2003-03-27 Shire Us Inc. Method for the manufacture of Anagrelide

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8133996B2 (en) 2007-02-06 2012-03-13 Cipla Limited Process for the preparation of ethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride
WO2010070318A1 (fr) * 2008-12-17 2010-06-24 Shire Llc Procédé de préparation d'anagrélide et de ses analogues
JP2012512237A (ja) * 2008-12-17 2012-05-31 シャイア エルエルシー アナグレリドの製造法
US8530651B2 (en) 2008-12-17 2013-09-10 Shire Llc Process for the preparation of anagrelide and analogues
CN107108464A (zh) * 2015-01-13 2017-08-29 日产化学工业株式会社 芳香族胺化合物的制造方法
CN107108463A (zh) * 2015-01-13 2017-08-29 日产化学工业株式会社 反应混合物中的锡化合物的处理方法
EP3246309A4 (fr) * 2015-01-13 2018-08-08 Nissan Chemical Industries, Ltd. Procédé de traitement d'un composé de l'étain dans un mélange réactionnel
EP3246308A4 (fr) * 2015-01-13 2018-08-08 Nissan Chemical Industries, Ltd. Procédé de fabrication de composé d'amine aromatique
CN107108463B (zh) * 2015-01-13 2019-05-17 日产化学工业株式会社 反应混合物中的锡化合物的处理方法
TWI697472B (zh) * 2015-01-13 2020-07-01 日商日產化學工業股份有限公司 芳香族胺化合物之製造方法
TWI758241B (zh) * 2015-01-13 2022-03-21 日商日產化學工業股份有限公司 反應混合物中之錫化合物之處理方法
WO2024180371A1 (fr) * 2023-03-02 2024-09-06 Mohammadi Ali Synthèse et purification du principe pharmaceutique actif de chlorhydrate d'anagrélide et de tous ses intermédiaires

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AU2008212668B2 (en) 2013-02-07
US8133996B2 (en) 2012-03-13
US20100075999A1 (en) 2010-03-25
NZ578561A (en) 2011-07-29
ZA200904906B (en) 2010-03-31
CA2675265A1 (fr) 2008-07-14
KR20090115151A (ko) 2009-11-04
AU2008212668A1 (en) 2008-08-14
AU2008212668A2 (en) 2009-08-27
JP2010518060A (ja) 2010-05-27
EP2114856A1 (fr) 2009-11-11

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